The problem of effecting repair of defective bones has plagued mankind for centuries. Until relatively recently, the only practical course was to immobilize broken bones and to rely on nature to effect regrowth of skeletal tissue into an injury. Only with the advent of the possibility of surgery has it been possible to utilize implanted bone substitutes, not only to replace injured or diseased bone structures, but also to repair congenital or degenerative defects in the skeletal structure.
A wide range of materials have since been utilized, and elaborate designs have been disclosed for replacements of entire portions of bones, for example hip joints (U.S. Pat. No. 3,820,167) and teeth (U.S. Pat. No. 4,186,486). Materials employed have included metals such as titanium (EPO Publication No. 0071242, published Feb. 9, 1983; U.S. Pat. No. 3,918,100), ceramics such as aluminum oxide (U.S. Pat. No. 3,919,723), shaped and treated bone (U.S. Pat. No. 3,318,774), and various bone preparations such as, for example, bone dust compacted into flexible mats (U.S. Pat. No. 2,621,145).
It has long been understood that skeletal structures have inorganic and organic components. The mineral component which, presumably, accounts for the strength and rigidity of bone structure is predominantly a form of calcium phosphate, hydroxyapatite. The organic component is chiefly composed of a single type of protein, collagen, which serves to impart a measure of resilience thus preventing the structures from being unduly brittle. As skeletal tissue is alive, of course, additional metabolically active organic components must be included in the structure, and it is these bone cells and their active metabolites which are responsible for the naturally occurring healing and maintenance processes.
However, since the major components of bone from a quantitative standpoint are collagen and ceramic, various reconstituted implant preparations involving mixtures of similar or different ceramic materials and various types of collagen preparations have also been employed. For example, see U.S. Pat. No. 3,443,261, Hayashi, K., et al, Arc Orthop Traumat Surg (1982) 99: 265; and U.S. Pat. No. 4,314,380).
It has been determined that bone tissue repair occurs by one of two alternative mechanisms, or a combination of both. In conductive repair, cells which are already committed to their character as bone cells (osteoprogenitor cells) move into the space of the defect from adjacent bone, and form bone directly. No special factors (other than non-specific nutrients) are required. In induction, however, this process is preceded by conversion of previously uncommitted multipotential cells into osteoprogenitor cells which first form cartilage that calcifies and degenerates and is replaced by bone. In order to acquire the capacity to do this, specific protein factors are required. The nature of these factors is not at present understood. For either conductive or inductive repair, it is required that the living tissue of the host provides the ultimate skeletal structure. Thus the implant which mediates these processes serves not as a substitute for the defective or removed bone, but rather as a matrix support for active replacement of the missing tissue.
Accordingly, attempts have been made to devise implants for defective skeletal tissue or lesions in bones and teeth which are intended precisely for this purpose. These implants do not attempt to mimic the composition of the missing bone, but rather to serve as a structural support and a guiding matrix for encroaching bone deposits derived ultimately from the adjacent fresh bone. These supports may provide only matrix support functions, i.e., mediate conductive repair, or may, in addition, include factors which stimulate the differentiation of uncommitted cells to osteoprogenitor cells by providing what are currently known as "osteogenesis factors" (OF) or "bone morphogenic proteins" (BMP). Because collagen is already a familiar material to the metabolically viable cells associated with bone growth, attempts have been made to use implants which are composed predominantly of collagen for both inductive and conductive bone repair.
For implants useful in inductive repair, U.S. Pat. No. 4,294,753 discloses a process for preparing a bone morphogenic protein. A purification procedure for an OF which is probably not identical to the BMP of the foregoing patent is disclosed in U.S. Pat. No. 4,434,094 issued Feb. 28, 1984. These factors reside naturally in bone, and preparations of demineralized bone particles, which are used in construction of implants, presumably release this factor in operable form. Both purified and unpurified forms of these factors have been used in various implants.
Other workers have disclosed the results of attempts to utilize collagen preparations alone as a matrix for conductive bone repair activities, i.e., preparations which do not contain factors for maturation of progenitor cells into osteogenic cells, and thus mediate conductive repair.
Krekeler, V. G., et al, J Oral Surg (1981) 10: Suppl. 1: 151 compared the utility of autologous spongiosa, a preparation of collagen (Collagenfleece.RTM., Pentapharm) and binding gelatin as fillings for peridontal defects in beagles. The preparations were simply packed into the bony cavities artificially created, and the healing processes followed by polychrome sequential labeling. Collagenfleece.RTM. was found to mediate the healing, but was less effective than the autologous spongiosa transplants.
The Collagenfleece.RTM. used in the preceding preparation is derived according to a procedure disclosed in U.S. Pat. No. 4,066,083 from pigskin. The skin is finely divided, degreased using detergent, washed, and digested with pepsin to give a viscous suspension, and the collagen precipitated by addition of saturated salt solution. The precipitate is suspended in acid, reprecipitated as a fibrous white precipitate in salt solution, washed as many times as desired, and desalted by washing with alcohol. The purified collagen is suspended in acid solution and freeze dried. It is sterilized by .gamma.-irradiation, which may degrade or cross link the preparation. This preparation is available commercially under the name Collagenfleece.RTM. and has been used in a number of other bone repair studies.
Joos, U., et al, Biomaterials (1980) 1: 23-26, utilized Collagenfleece.RTM. as an implant in artificially damaged rabbit mandibles and found that after 2 weeks, the defects were filled with cancellous bone particles and showed complete ossification after 4 weeks. Zetzmann, D., et al, Schweiz Mschr Sabnhelik (1982) 92: 119 also achieved bone regeneration in facial surgery upon use of Collagenfleece.RTM. as an implant. Springorum, H. W., et al, Z Orthop (1977) 115: 686 obtained similar results using Collagenfleece.RTM. in a cortical layer defect.
Jaffee, A., et al, Archs Oral Biol (1978) 23: 415; ibid. (1982) 27: 999 reported successful anchoring of acrylic tooth implants in dogs using collagen solutions which were prepared from dog skin by extraction with acetic acid and trichloroacetic acid/ethanol purification. The successful anchoring of the implants was intact after a year.
Cucin, R. L., et al, New York State Journal of Medicine (1979) 1856 used atelopeptide collagen from calf skin, which had been gamma irradiated, for rib repair in rabbits and, when supported by gelatin sponge material or with autologous bone dust, to repair skull holes in dogs.
A preparation of collagen, presumably still containing the teleopeptides, and cross-linked by gamma irradiation was employed in filling tooth pulp cavities and as an under the skin "bone replacement" implant as disclosed in, respectively, EPO Publication No. 0012443 published June 25, 1980 and EPO publication No. 0012959, published July 9, 1980.
None of the foregoing collagen repair procedures are completely successful. Either inflammation occurs, particularly where xenogeneic collagen is used, or healing is unsatisfactory. The present invention provides an implantable collagen preparation which is capable of conducting the ingrowing bone repair tissue from dedicated bone cells into the defect whose repair is desired. Because xenogeneic collagen can be used, large amounts are obtainable and the method can be widely applied. In addition, the invention provides bone repair compositions which offer great versatility in being adaptable to a wide range of stress-bearing requirements.